Neuregulins (NRGs) and their receptors constitute a growth factor-receptor tyrosine kinase system for cell-cell signalling that has been implicated in organogenesis in nerve, muscle, epithelia, and other tissues (Lemke, Mol. Cell. Neurosci. 7: 247-262, 1996; Burden et al., Neuron 18: 847-855, 1997). The three known NRG genes, NRG-1, NRG-2, and NRG-3, map to distinct chromosomal loci (Pinkas-Kramarski et al., Proc. Natl. Acad. Sci. USA 91: 9387-91, 1994; Carraway et al., Nature 387: 512-516, 1997; Chang et al., Nature 387:509-512, 1997; and Zhang et al., Proc. Natl. Acad. Sci. USA 94: 9562-9567, 1997), and collectively encode a diverse array of NRG proteins. The NRG protein family includes at least 20 (and perhaps 50 or more) secreted and membrane-bound isoforms containing epidermal growth factor-like (EGFL), immunoglobulin (Ig), and other recognizable domains.
The most thoroughly studied NRG proteins to date are the gene products of NRG-1, which include a group of approximately 15 distinct structurally-related isoforms (Lemke, Mol. Cell. Neurosci. 7: 247-262, 1996 and Peles and Yarden, BioEssays 15: 815-824, 1993). Isoforms of NRG-1 include Neu Differentiation Factor (NDF; Peles et al., Cell 69, 205-216, 1992 and Wen et al., Cell 69, 559-572, 1992), Heregulin (HRG; Holmes et al., Science 256: 1205-1210, 1992), Acetylcholine Receptor Inducing Activity (ARIA; Falls et al., Cell 72: 801-815, 1993), and the glial growth factors GGF1, GGF2, and GGF3 (Marchionni et al., Nature 362: 312-8, 1993).
The NRG-2 gene was identified by homology cloning (Chang et al., Nature 387:509-512, 1997; Carraway et al., Nature 387:512-516, 1997; and Higashiyama et al., J. Biochem. 122: 675-680, 1997) and through genomic approaches (Busfield et al., Mol. Cell. Biol. 17:4007-4014, 1997). NRG-2 isoforms include Neural-and Thymus-Derived Activator of erbB Kinases (NTAK; Genbank Accession No. AB005060), Divergent of Neuregulin (Don-1), and Cerebellum-Derived Growth Factor (CDGF; PCT application WO 97/09425). Cells expressing erbB4 or erbB2/erbB4 receptors may show a particularly robust response to NRG-2 (Pinkas-Kramarski et al., Mol. Cell. Biol. 18: 6090-6101, 1998). The NRG-3 gene product (Zhang et al., Proc. Natl. Acad. Sci. USA 94: 9562-9567, 1997) is also known to bind and activate erbB4 receptors (Hijazi et al., Int. J. Oncol. 13:1061-1067, 1998).
The EGFL domain, present at the core of NRG isoforms, is required for binding and activating NRG receptors, which belong to the epidermal growth factor receptor (EGFR) family, and include EGFR (or erbB1), erbB2, erbB3, and erbB4, also known as HER1 through HER4, respectively, in humans (Meyer et al., Development 124: 3575-3586, 1997; Orr-Urtreger et al., Proc. Natl. Acad. Sci. USA 90: 1867-71, 1993; Marchionni et al., Nature 362: 312-8, 1993; Chen et al., J. Comp. Neurol. 349: 389-400, 1994; Corfas et al., Neuron 14: 103-115, 1995; Meyer et al., Proc. Natl. Acad. Sci. USA 91:1064-1068, 1994; and Pinkas-Kramarski et al., Oncogene 15: 2803-2815, 1997). High-affinity binding of the NRGs may be mediated principally via either the erbB3 or erbB4 receptors. Binding of NRG ligands leads to dimerization with other erbB subunits and transactivation by phosphorylation on specific tyrosine residues.
NRG proteins have diverse biological properties, making them potentially useful in the development of novel therapies for a wide range of diseases and disorders.